Abstracts

James Appel, Ph.D.
LSD, Serotonin (5-HT), and the Evolution of a Behavioral Assay.

More than 25 years of research in the Behavioral Pharmacology Laboratory (University of South Carolina), which was supported by NIDA and encouraged and facilitated by Roger Brown, has indicated that serotonergic neuronal systems (5-HT2A) are involved in the discriminative stimulus effects of LSD. However, this conclusion, along with the hypothesis that substitution for LSD in rats and other animals predicts hallucinogenic potency in humans, has had to be tempered by the observation that “false-positives” sometimes occur in drug discrimination experiments; that is, administration of drugs such as lisuride, quipazine, and yohimbine, which are neither primarily serotonergic nor have LSD-like effects in humans, substitute for LSD. We have found that such false-positives can be eliminated by using training procedures that are more selective than the drug vs. no-drug procedure typically used in drug discrimination experiments; these include drug vs. drug (LSD-lisuride) and, more recently, drug vs. other drug (LSD-saline, cocaine, pentobarbital) discriminations.

The relevance of memory and reward to factors that control substance abuse is becoming more obvious as research drives toward an understanding of how these two factors operate in the brain. The research supported and fostered by Roger Brown, Ph.D., provided much of the impetus for understanding how these processes become usurped in cases of drug addiction and abuse. Current insights into the actions of abused substances, such as marijuana and cocaine, on memory and reward will be presented.

Ample evidence has accumulated indicating that dopamine (DA) is implicated in the brain reward systems and that DA is directly or indirectly involved in the acute reinforcing actions of ethanol, although other neurochemical systems including GABA, glutamate, serotonin, and opioid peptides also appear to participate in orchestrating the reward profile of ethanol.

The molecular events underlying the DA-enhancing properties of ethanol are largely unknown, but ethanol has been shown to directly interfere with ionic flux through several multisubunit, ligand-gated ion channels, including nicotinic acetylcholine receptors (nAChR). We have previously reported that chronic ethanol administration can produce differential Bmax changes in 3H-nicotine binding in various brain regions. We have now obtained both behavioral and neurochemical data indicating that the DA-activating and reinforcing properties of ethanol may in fact involve activation of central nAChR, especially those located in the ventral tegmental area. Studies aiming at defining the nAChR subpopulation(s) involved in mediating the effects of ethanol have revealed that the _3_2 or _6, but not the _4_2 or _7, subunits could represent targets for developing new drugs for treatment of alcoholism.

Over the past decade, data collected in our laboratory has demonstrated that self-administered cocaine produces opponent-process-like behavioral effects. Animals running a straight alley once each day for intravenous (IV) cocaine develop over trials an approach-avoidance conflict about re-entering the goal box. This behavioral ambivalence appears to stem from concurrent rewarding and anxiogenic properties of the drug—both of which are associated with the goal box. The opponent-process actions of cocaine were more directly observed in subsequent conditioned place-preference studies where the initial immediate effects of IV cocaine were shown to be reinforcing, while the state present 15 minute postinjection was found to be aversive. In more recent work, we have shown that alcohol or heroin can reduce the negative/anxiogenic properties of cocaine and thereby account for the frequent coabuse of these compounds with cocaine.

The pain-relieving efficacy of opioid derivatives depends on the action of a pain-modulating circuit with connections in the limbic forebrain, midbrain, and medulla. This circuit is linked by neurons that release endogenous opioids. The modulating circuit exerts bidirectional control over pain-transmitting neurons at the first central synapse. Understanding the connectivity of this circuit has provided us with profound insights into processes such as tolerance and physical dependence. In addition, research in this area has helped us to understand how psychological processes such as attention and expectancy can alter perceived pain intensity in human subjects.

Gerald F. Gebhart, Ph.D.
Descending Modulation of Pain

Experimental interest in the descending modulation of spinal cord function has a long history. Sherrington and coworkers first documented that the nociceptive flexion reflex is enhanced following spinal cord transection. Later investigations examined modulation of flexion reflexes evoked by activation of “flexion reflex afferents,” which was superseded by interest in nociceptive processing in the spinal dorsal horn. The impetus for such studies arose after Reynolds reported that focal electrical stimulation in the midbrain periaqueductal gray (PAG) of the awake rat produced a profound analgesia, a finding soon reproduced in man. Subsequently, stimulation in various regions of brain has been shown to produce robust antinociception in many species, many of which coincide with sites at which microinjection of morphine produces antinociception. Compelling anatomical, electrophysiological, and pharmacological evidence has established the rostroventromedial medulla as an integral relay in descending modulation of nociception, including that elicited by PAG stimulation.

Although the principal focus of investigation has been on inhibitory modulation of spinal nociceptive processes, it has been appreciated for some time that brainstem stimulation also can enhance/facilitate spinal nociceptive processes. Ke Ren first systematically investigated the potential pronociceptive aspect of descending modulation while a student in the lab in the late 1980s. We subsequently established, with support from NIDA, that descending inhibitory and facilitatory influences were pharmacologically and anatomically distinct. It is now widely appreciated that modulation of spinal nociception from the brainstem can be facilitatory or inhibitory and accumulating evidence suggests that descending facilitatory influences may contribute to the development and maintenance of hyperalgesia following peripheral tissue inflammation. We have previously proposed that chronic pain states may be sustained by active facilitatory influences from the brainstem. Recent findings will be summarized.

The stimulus-independent sustained activation of prefrontal neurons and their content-specific coding of information constitute the fundamental cellular basis of the brain's working memory functions. We have hypothesized that the property of persistent activity is mediated in part by recurrent excitation among pyramidal neurons in local prefrontal circuits. Evidence from work in cortical slices (Gao et al., 2001; Gao and Goldman-Rakic, 2003) and in the behaving primate (Williams and Goldman-Rakic, 1995; Constantinidis et al., 2001) will show how dopamine modulates this and other elemental neuronal interactions critical for working memory function.

Gao, W.-J., Krimer, L.S., and Goldman-Rakic, P.S. (2001) Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proceedings of the National Academy of Sciences of the United States of America 98:295-300.

Gao, W.-J. and Goldman-Rakic, P.S. (2003) Selective modulation of excitatory and inhibitory microcircuits by dopamine. Proceedings of the National Academy of Sciences of the United States of America 100:2836-2841.

This lecture will focus on the habit system of the brain and highlight research directed towards understanding how we make and break habits. Habits are semiautomatic routines that are highly advantageous because they free us to think and attend to the world, but the habit system can also be hijacked by disease and drug exposure.

John A. Harvey, Ph.D.
Cocaine Effects on the Developing Brain: Current Status

The long-term effects of in utero exposure to cocaine will be described in terms of anatomical, neurochemical, physiological, and behavioral consequences in experimental animals and compared with current findings in clinical studies. A model describing the basic mechanisms through which cocaine affects the developing brain and produces long-term behavioral deficits will be presented.

The work in this laboratory has focused on understanding the basic neurobiological mechanisms underlying appetitive motivation. Studies have focused primarily on the role of the nucleus accumbens and its associated circuitry in the control of reward learning and food intake. This endeavor has included investigations of glutamate, GABA, dopamine, and opioid systems within this network. Evidence is provided that describes a key cortico-ventral striatal-hypothalamic pathway in the control of food motivation, and a parallel pathway linked to voluntary motor circuits that controls adaptive instrumental learning. Drug-induced alterations in these brain systems mediating natural rewards may contribute to addiction.

George F. Koob, Ph.D.
Neurobiological Mechanisms in the Transition From Drug Use to Drug Dependence

Drug addiction is a chronic relapsing disorder characterized by compulsive drug intake, loss of control over intake, and impairment in social and occupational function. Animal models have been developed for various stages of the addiction cycle with a focus in our work on the motivational effects of drug dependence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework by which to identify the neurobiologic mechanisms involved in the development of drug addiction. Neuropharmacologic studies in animal models have provided evidence for the dysregulation of specific neurochemical mechanisms in specific brain reward and stress circuits that provide the negative motivational state that drives addiction. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic drug ingestion with genetic vulnerability, but also provides the key by which to translate advances in animal studies to the human condition.

The development of the brain-stimulation reward for the study of the rewarding effects of drugs and the extent that it is related to sensitization of morphine-induced oral stereotypy will be briefly reviewed.

Evidence for protracted changes in brain and behavior, including results in aged rats, and the relevance of these models and findings for understanding mechanisms of abuse and relapse to opiate use will be presented.

Klaus A. Miczek, Ph.D.
Social Experiences: Amines and Peptides in the Mesocorticolimbic System

Salient social experiences trigger immediate early gene expression that is large, long-lasting, restricted to cells in the core areas of the neuroaxis, and critical to the fundamental processes of neuroadaptation. These biologically significant stressors activate cells in the endogenous aminergic and peptidergic systems leading ultimately to sensitization as well as tolerance. Several lines of evidence support the hypothesis that this cascade of cellular events is the basis for neural dysregulation leading to out-of-control drug taking. Examples from our ongoing work on the neural circuits for social stress and those mediating intensely rewarding activities such as compulsive cocaine administration point to considerable overlap between these neural circuits, and identifies targets for pharmacotherapeutic intervention in stress disorders and drug abuse.

Prolonged exposure to cocaine produces widespread dysregulation in dopamine systems. Using a nonhuman primate model of substance abuse, we have examined the temporal progression of the adaptations in dopamine transporters and receptors as experience with cocaine advances from initial to chronic stages of drug exposure. With more extended experience with cocaine, there is progressive involvement of broader aspects of striatal territory spreading beyond limbic domains into areas concerned with the processing of cognitive and motor information. The development of these adaptations reflects the intrinsic and extrinsic anatomical connections of the striatum and suggests that cocaine may have a widening influence on more aspects of behavior.

The neurotoxic potential of methamphetamine toward brain dopamine neurons was discovered almost 3 decades ago. Since then, considerable progress has been made toward understanding the basic and clinical implications of this important discovery. This presentation will first highlight major research accomplishments to date, including the extension of methamphetamine findings to other amphetamine analogs and the recent demonstrations by several groups that findings of neuronal injury in methamphetamine-treated animals may generalize to human beings. Significant remaining challenges will then be identified. These include delineation of underlying mechanisms, understanding of species response differences, identification of functional consequences, and anticipation of possible tardive effects in humans previously exposed to neurotoxic amphetamine analogs.

In most cocaine self-administration studies with rats, animals are given access to drug for only a few hours per day (typically 1-3 hours). Under these conditions, behavioral characteristics of cocaine self-administration do not change; levels and patterns of cocaine intake are stable and remain so over several months of testing. These characteristics have been extraordinarily useful in studies of drug reinforcement; however it appears that such limited access procedures do not model critical features of the addiction process such as a progression toward binge-abstinence patterns of drug use and an increased motivation to seek and use cocaine. Recently we have developed procedures that allow access to cocaine throughout the light/dark cycle for many weeks without toxicity. These include access to cocaine occurs during 10-minute trials that are initiated at regular intervals and presentation of 2 or 3 trials.

Recent studies suggest the involvement of cholinergic neurons in the brain processes underlying reinforcement. The involvement of cholinergic neurons in opiate and cocaine reinforcement have been assessed by measuring the turnover rates of acetylcholine (ACh) in brain regions of rats intravenously self-administering morphine or cocaine and in yoked drug and yoked vehicle-infused controls. ACh turnover changes implicate the involvement of cholinergic neurons in the diagonal band-preoptic region, the medial septum, and several brainstem nuclei and interneurons in the nucleus accumbens, caudate-putamen, and ventral pallidum in the processes underlying self-administration. The role of ACh-releasing neurons in the diagonal band, ventral pallidum, and nucleus accumbens have been further investigated using a selective cholinergic neurotoxin to remove these cells and assess effects upon cocaine self-administration. These data support the involvement of cholinergic neurons in the ventral pallidum and diagonal band in the processes that underlie cocaine self-administration. The identified cholinergic neuronal systems may have a broader role in the brain processes for natural reinforcers (i.e. food, water, etc.) since drugs of abuse are believed to produce reinforcing effects through these systems.

George R. Uhl, M.D., Ph.D.
Drug Abuse Genetics: Monoamines and Beyond

My talk will begin with monoamine-based thinking about the molecular and molecular genetic bases of acute stimulant reward. I will then describe current remarkably convergent data that support influences of common, polygenic human allelic variants on human addiction vulnerability. I will discuss an emerging picture: Studying these variants may well take us far beyond catecholamine brain mechanisms and acute drug reward and may move us toward improved understanding of both drug pharmacodynamics and the learning-like processes that underlie much of addiction.

Evidence will be presented showing that manipulations that produce sensitization of nucleus accumbens dopamine overflow enhance the pursuit and self-administration of psychomotor stimulant drugs. Procedures known to prevent the induction of this sensitization also prevent the facilitation of drug-taking. Finally, manipulations that increase nucleus accumbens dopamine overflow acutely, but fail to produce sensitization of this effect are not associated with the subsequent enhancement of self-administration. These results indicate a direct relationship between the sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of psychomotor stimulant drugs.

Roy Wise, Ph.D.
Brain Reward Circuitry and Addiction

Interest in the brain mechanisms of addiction was sparked by the discovery that rats will work for direct electrical stimulation of reward circuitry in the brain. Following the report that the behavior of rats working for intravenous amphetamine paralleled that of rats working for hypothalamic brain stimulation, cross-fertilization between behavioral pharmacologists and physiological psychologists was fostered at NIDA. Parallel studies of the two rewards led to the identification of brain dopamine as a central transmitter of reward-related messages, and subsequent characterization of drug-reward circuitry has focused on the mesolimbic dopamine system and its afferents and efferents.

What's New Contents

Sponsored by
National Institute on Drug Abuse
National Institutes of Health
Department of Health and Human Services

In partnership with
The New York CTN Node/New York University School of Medicine
The Long Island CTN Node/Columbia University and New York State Psychiatric Institute
New York State Office of Alcoholism and Substance Abuse Services
Alcoholism and Substance Abuse Providers of NYS
Northeast Addiction Technology Transfer Center (ATTC)
New York State Practice Improvement Collaborative (PIC)